High Selectivity For Cancer Cells Research Articles

Efficacy assessment of a novel pan-RAS inhibitor in KRAS-mutant and wild type colorectal 3D bioprinted organoid tumor tissue.

91 Background: Colorectal cancer (CRC) is the third leading type of cancer worldwide, with ~150,000 new cases in the US annually and a grim 14% 5-year survival for patients diagnosed at a late stage. A lack of treatment options leads to persistently poor prognosis for patients with advanced stage disease. KRAS mutations are well known drivers of CRC and other GI cancers. Multiple KRAS mutations occur in CRC, including G12D (34%), G12V (21%), G13D (20%), G12C (8%), and others (18%). Existing KRAS-targeted therapies have limited use in CRC, underscoring the need for pan-RAS inhibitors in treating CRC and other RAS driven cancers. Objective: Assess activity of ADT-007, our pan-RAS inhibitor, on wild-type (WT) and KRAS-mutant 3D bioprinted organoid tumor (BOT) tissue using our high-throughput ex vivo platform. Methods: Using previously established bioprinting protocols, WT and mutant BOTs were printed with HT29 and HCT116 cells, respectively. HT29 is an established human WT CRC cell line with known sensitivity to proteosome and survivin inhibitors. HCT116 is a KRASG13D mutant human CRC cell line. 3 sets of BOTs were generated and acclimated for 24h. One set was treated for 72h with proteosome inhibitor Bortezomib, another with survivin inhibitor YM155, and the third with our novel pan-RAS inhibitor ADT-007. Dose response curves were generated from both conventional ATP luminescence readouts and high-content imaging. Results: BOT tissue microarchitecture was validated and >200 µm diffusion in BOTs was confirmed using high-content imaging. Differential response was quantified using Cell TiterGlo endpoint assay as well as advanced image processing of high-content live/dead nuclear stained images captured at multiple z-plains. ADT-007 IC50 was found to be substantially lower for mutant HCT116 compared to that for WT HT29 cell line BOTs, which was consistent with separately conducted in vitro and in vivo studies. Conclusions: A pan-RAS inhibitor, such as ADT-007 with high selectivity for cancer cells with activated RAS that is not limited to a specific KRAS mutant allele or RAS isozyme, could have broader use for CRC and other RAS-driven cancers. Further, due to their potential to replicate biophysical characteristics of a tumor and its microenvironment, BOT based precision and personalized medicine platforms can provide more accurate drug efficacy readout compared to in vitro cancer models.

Phytochemical Analysis, In vitro Assessment of Antioxidant Properties and Cytotoxic Potential of Thymus capitatus Essential Oil

Essential oils (EOs) of medicinal plants became a matter of interest in scientific research because of their potential of utilization for several therapeutic purposes, The EO of Thymus capitatus has been traditionally used in treatment of several conditions related to skin, muscles, and respiratory system, to reduce fever, and to stimulate menstrual flow in addition to its anti-bacterial properties. To chemically analyze the components of the EO of Thymus capitatus and to evaluate its anti-cancerous and anti-oxidant activity on breast cancer cells (T47D), colorectal adenocarcinoma cells (CACO2), and normal human fibroblasts (MRC5). The EOs were extracted by hydro-distillation. Gas chromatography and mass spectrometry were used to analyze the extracts. Cell viability was assessed using three different assays; MTT, trypan blue and neutral red assays. Antioxidant activity was assessed using DPPH scavenging assay. Cell apoptosis was assessed using DNA fragmentation tests and Annexin V-propidium iodide assay. Morphological analysis of cells was assessed using light microscopy and DAPI staining. Twenty-two different compounds were identified in the essential oil of T. capitatus leaves including Thymol (44.34%) and Carvacrol (38.89%) in addition to 20 minor components. The oil extract exhibited a significant inhibitory action on the three cell lines. The viability assays showed significantly higher (p<0.05) IC50 in the fibroblast cell line than the other two cell lines. The selectivity index was higher in T47D cell line compared to CACO II cell line. For apoptosis assessment, DNA fragmentation in T47D cells was significantly correlated with the extract concentration. The membrane polarity was disrupted in an increasing manner (15.60±1.13, 35.73±1.69 and 46.53±2.51) as the extract concentration (20.22, 40.45, and 80.9µg/ml, respectively) increased. On the cellular level, morphological changes including cell shrinkage, chromatin condensation and nuclear fragmentation in addition to marginalization of chromatin, vacuolization of cytoplasm and formation of micronuclei was clearly visible. The extract showed high anti-oxidant activity with an IC50 of 6.4µg/ml. Anti-oxidant activity was dose-dependent; double IC50 (80.9µg/ml) exhibited the highest antioxidant activity whereas the lowest antioxidant activity was observed for the ½ IC50 (20.225µg/ml). The oil extract exerted an inhibitory action lipid peroxidation. Thymus capitatus EO is a potential anti-oxidant and anti-neoplastic agent against breast and colon carcinomas due to its high selectivity for cancer cells compared to normal cell lines.

3-(1,2,3-Triazol-4-yl)-β-Carbolines and 3-(1H-Tetrazol-5-yl)-β-Carbolines: Synthesis and Evaluation as Anticancer Agents.

Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was used in the synthesis of 3-(1,2,3-triazol-4-yl)-β-carbolines via Pictet-Spengler condensation followed by an oxidative step. A library of compounds, including the novel 3-(1,2,3-triazol-4-yl)-β-carbolines as well as methyl β-carboline-3-carboxylate and 3-tetrazolyl-β-carboline derivatives, was evaluated for their antiproliferative activity against colorectal cancer cell lines. The 3-(1H-tetrazol-5-yl)-β-carbolines stood out as the most active compounds, with values of half-maximal inhibitory concentration (IC50) ranging from 3.3 µM to 9.6 µM against colorectal adenocarcinoma HCT116 and HT29 cell lines. The results also revealed a mechanism of action independent of the p53 pathway. Further studies with the 3-tetrazolyl-β-carboline derivative, which showed high selectivity for cancer cells, revealed IC50 values below 8 μM against pancreatic adenocarcinoma PANC-1, melanoma A375, hepatocarcinoma HEPG2, and breast adenocarcinoma MCF-7 cell lines. Collectively, this work discloses the 3-tetrazolyl-β-carboline derivative as a promising anticancer agent worthy of being further explored in future works.

A New Naphthopyran Derivative Combines c-Myb Inhibition, Microtubule-Targeting Effects, and Antiangiogenic Properties.

Based on the promising c-Myb inhibitor 1b, a series of 2-amino-4-aryl-4H-naphtho[1,2-b]pyran-3-carbonitriles (1a, 2a-q, 3a-g) were repurposed or newly synthesized via a three-component reaction of 1-naphthol, and various aryl aldehydes and malononitrile and screened for their c-Myb inhibitory activities. 1b also served as a lead compound for seven new naphthopyran derivatives (3a-f), which were cytotoxic with nanomolar IC50 values, to inhibit the polymerization of tubulin, and to destabilize microtubules in living cells. Especially, the alkyne 3f, originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed. A strong G2/M cell cycle arrest was detected, which resulted in a distinct increase in sub-G1 cells through the induction of effector caspases 3 and 7. Inhibition of angiogenesis was confirmed in vitro and in vivo. In summary, 3f was found to be a pleiotropic compound with high selectivity for cancer cells, combining c-Myb inhibitory, microtubule destabilizing, and antiangiogenic effects.

Discovery of novel IDH1-R132C inhibitors through structure-based virtual screening.

Isocitrate dehydrogenase (IDH) belongs to a family of enzymes involved in glycometabolism. It is found in many living organisms and is one of the most mutated metabolic enzymes. In the current study, we identified novel IDH1-R132C inhibitors using docking-based virtual screening and cellular inhibition assays. A total of 100 molecules with high docking scores were obtained from docking-based virtual screening. The cellular inhibition assay demonstrated five compounds at a concentration of 10 μM could inhibit cancer cells harboring the IDH1-R132C mutation proliferation by > 50%. The compound (T001-0657) showed the most potent effect against cancer cells harboring the IDH1-R132C mutation with a half-maximal inhibitory concentration (IC50) value of 1.311 μM. It also showed a cytotoxic effect against cancer cells with wild-type IDH1 and normal cells with IC50 values of 49.041 μM and >50 μM, respectively. Molecular dynamics simulations were performed to investigate the stability of the kinase structure binding of allosteric inhibitor compound A and the identified compound T001-0657 binds to IDH1-R132C. Root-mean-square deviation, root-mean-square fluctuation, and binding free energy calculations showed that both compounds bind tightly to IDH1-R132C. In conclusion, the compound identified in this study had high selectivity for cancer cells harboring IDH1-R132C mutation and could be considered a promising hit compound for further development of IDH1-R132C inhibitors.

Novel oxygen-generation from electrospun nanofibrous scaffolds with anticancer properties: synthesis of PMMA-conjugate PVP-H2O2 nanofibers, characterization, and in vitro bio-evaluation tests.

Released oxygen plays a critical role in reducing destructive tumor behavior. This study aims to utilize decomposed hydrogen peroxide as an oxygen source by conjugating it with polyvinylpyrrolidone (PVP). PVP–hydrogen peroxide complex (PHP) composed of different ratios of (PVP : H2O2) (0.5 : 1, 1 : 1, 1 : 1.5, 1 : 5, and 1 : 10) were successfully synthesized. PHP complex with a ratio of 1 : 1.5 was chosen as the optimized ratio, and it was incorporated into the polymethyl methacrylate (PMMA) nanofibrous scaffold via the electrospinning technique. Results have revealed that the PMMA–10% PHP complex provided a significant morphological structure of nanofibrous scaffolds. The mechanical properties of PMMA–10% PHP nanofibers showed the most suitable mechanical features such as Young's modulus, elongation-at-break (%), and maximum strength, in addition to the highest degree of swelling. All PHP complex scaffolds released oxygen in a sustained manner. However, the PMMA–10% PHP complex gave the highest concentration of released-oxygen with (∼8.9 mg L−1, after 2.5 h). PMMA–10% PHP nanofibers provided an ideal model for released-oxygen scaffold with anti-cancer effect and high selectivity for cancer cells, especially for breast cancer cells. Nanofibrous scaffolds with different composition revealed high cell viability for normal cells. Such outcomes support the suitability of using synthesized nanofibrous scaffolds as released-oxygen biomaterials to enhance cancer cells' sensitivity and maximize the treatment effect.

Antineoplastic activity of a novel ruthenium complex against human hepatocellular carcinoma (HepG2) and human cervical adenocarcinoma (HeLa) cells

Novel metal complexes have received much attention recently because of their potential anticancer activity. Notably, ruthenium-based complexes have emerged as good alternatives to the currently used platinum-based drugs for cancer therapy, with less toxicity and fewer side effects. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidative states, low toxicity, and high selectivity for cancer cells. The present study evaluated the cytotoxic effects of a ruthenium complex, namely cis-[Ru(1,10-phenanthroline)2(imidazole)2]2+ (RuC), on human hepatocellular carcinoma (HepG2) and human cervical adenocarcinoma (HeLa) cells and analyzed metabolic parameters. RuC reduced HepG2 and HeLa cell viability at all tested concentrations (10, 50, and 100 nmol/L) at 48 h of incubation, based on the MTT, Crystal violet, and neutral red assays. The proliferation capacity of HepG2 cells did not recover, whereas HeLa cell proliferation partially recovered after RuC treatment. RuC also inhibited all states of cell respiration and increased the levels of the metabolites pyruvate and lactate in both cell lines. The cytotoxicity of RuC was higher than cisplatin (positive control) in both lineages. These results indicate that RuC affects metabolic functions that are related to the energy provision and viability of HepG2 and HeLa cells and is a promising candidate for further investigations that utilize models of human cervical adenocarcinoma and mainly hepatocellular carcinoma.

Design of ruthenium-albumin hydrogel for cancer therapeutics and luminescent imaging

Improving cell uptake of metal compounds has became an important goal in the field of metal-based anticancer agents. This may combat platinum resistance and side effects seen commonly in current anticancer chemotherapy regimes. Here, we explore a novel degradable ruthenium-albumin hydrogel, which shows strong luminescence for cell imaging and high selectivity for cancer cells versus non-cancer cells. This is an early indication of the possibility of reducing unwanted side effects of metals by using bovine serum albumin hydrogel as a delivery strategy. This work provides a strong basis for development of a new class of metal-based cancer therapeutic agents.

Cancer Stem Cells: Concepts, Challenges, and Opportunities for Cancer Therapy.

Cancer stem cells (CSCs) are a subpopulation of cancer cells with self-renewal capacity, thatfuel tumor growth and contribute to the heterogeneous nature of tumors. First identified in hematological malignancies, CSC populations have to date been proposed in solid tumors in various organs. In vitro and in vivo assays, mouse genetic models, and more recently single-cell sequencing technologies and other '-omics' methodologies have not only facilitated the identification of novel CSC populations but also revealed and clarified novel properties of CSCs. Increasingly, both cell-autonomous and CSC niche factors are recognized as important contributors of CSC properties. The deepened understanding of CSC properties and characteristics would enable and facilitate the rational design of CSC-specific therapeutics that would, ideally, have high selectivity for cancer cells, eliminate tumor bulk, and prevent tumor recurrence. Addressing these issues would form some of the key challenges of the CSC research field in the coming years.

Correction: A hypoxia-specific and mitochondria-targeted anticancer theranostic agent with high selectivity for cancer cells.

Correction for 'A hypoxia-specific and mitochondria-targeted anticancer theranostic agent with high selectivity for cancer cells' by Mingxing Hu et al., J. Mater. Chem. B, 2018, 6, 2413-2416.

A hypoxia-specific and mitochondria-targeted anticancer theranostic agent with high selectivity for cancer cells.

Herein, a novel soluble mitochondria-targeted theranostic compound, HMX-1, was presented, which was selectively activated under hypoxia with excellent mitochondria-targeting ability at the cellular level, accompanied by a dramatic increase in the fluorescence intensity. Moreover, its anti-cancer efficiency was certified both in vitro and in vivo.

Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential

In this paper, the synthesis of fourteen alkylamino and arylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone is described. Branched, cyclic, allylic and benzylic alkylamino/arylamino groups were introduced into the quinone moiety. For all the obtained derivatives, their biological activity and redox properties were studied. The cytotoxic activity of the synthesized derivatives towards multidrug resistant (MDR) human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) was investigated. The antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungal cultures was determined. Some of the synthesized derivatives showed selectivity for cancer cells, including MDR cells. Regarding their cell death induction potential, the most promising compounds were allylamino derivatives, preferentially triggering apoptosis, with high selectivity for cancer cells, including MDR cells. Several compounds showed promising antimicrobial activity, comparable to those of commercial antibiotic and antimycotic agents.

Tumor-specific delivery of doxorubicin through conjugation of pH-responsive peptide for overcoming drug resistance in cancer

The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.

A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells.

Mitochondria have recently emerged as novel targets for cancer therapy due to its important roles in fundamental cellular function. Discovery of new chemotherapeutic agents that allow for simultaneous treatment and visualization of cancer is urgent. Herein, we demonstrate a novel bifunctional mitochondria-targeted anticancer agent (FPB), exhibiting both imaging capability and anticancer activity. It can selectively accumulate in mitochondria and induce cell apoptosis. Notably, it results in much higher toxicity toward cancer cells owing to much higher uptake by cancer cells. These features make it highly attractive in cancer imaging and treatment.

Histidine-iridium(III) coordination-based peptide luminogenic cyclization and cyclo-RGD peptides for cancer-cell targeting.

In the field of peptide drug discovery, structural constraining and fluorescent labeling are two sought-after techniques important for both basic research and pharmaceutical development. In this work, we describe an easy-to-use approach for simultaneous peptide cyclization and luminescent labeling based on iridium(III)-histidine coordination (Ir-HH cyclization). Using a series of model peptides with histidine flanking each terminus, the binding activity and reaction kinetics of Ir-HH cyclization of different ring sizes were characterized. In the series, Ir-HAnH (n = 2, 3) with moderate ring sizes provides appropriate flexibility and proper distance between histidines for cyclic formation, which leads to the best binding affinity and structural stability in physiological conditions, as compared to other Ir-HH-cyclized peptides with smaller (n = 0, 1) or larger (n = 4, 5) ring sizes. Ir-HRGDH, an Ir-HH-cyclized peptide containing integrin targeting motif Arg-Gly-Asp (RGD), showed better targeting affinity than its linear form and enhanced membrane permeability in comparison with fluorescein-labeled cyclic RGDyK peptide. Cell death inducing peptide KLA-linked Ir-HRGDH (Ir-HRGDH-KLA) showed dramatically enhanced cytotoxicity and high selectivity for cancer cells versus noncancer cells. These data demonstrate that the method conveniently combines structural constraining of peptides with luminescent imaging capabilities, which facilitates functional and intracellular characterization of potential peptide-based drug leads, thus introducing a new tool to meet emerging needs in medicinal research.

Selective Induction of Cancer Cell Death by Targeted Granzyme B

The potential utility of immunotoxins for cancer therapy has convincingly been demonstrated in clinical studies. Nevertheless, the high immunogenicity of their bacterial toxin domain represents a critical limitation, and has prompted the evaluation of cell-death inducing proteins of human origin as a basis for less immunogenic immunotoxin-like molecules. In this review, we focus on the current status and future prospects of targeted fusion proteins for cancer therapy that employ granzyme B (GrB) from cytotoxic lymphocytes as a cytotoxic moiety. Naturally, this serine protease plays a critical role in the immune defense by inducing apoptotic target cell death upon cleavage of intracellular substrates. Advances in understanding of the structure and function of GrB enabled the generation of chimeric fusion proteins that carry a heterologous cell binding domain for recognition of tumor-associated cell surface antigens. These hybrid molecules display high selectivity for cancer cells, with cell killing activities similar to that of corresponding recombinant toxins. Recent findings have helped to understand and circumvent intrinsic cell binding of GrB and susceptibility of the enzyme to inhibition by serpins. This now allows the rational design of optimized GrB derivatives that avoid sequestration by binding to non-target tissues, limit off-target effects, and overcome resistance mechanisms in tumor cells.

Efficient Intracellular Delivery of Camptothecin by Silica/Titania Hollow Nanoparticles

Silica/titania hollow nanoparticles (HNPs) with 50 nm were fabricated by using the dissolution and redeposition method and modified with anti-[human epidermal growth factor receptor 2] monoclonal antibody (herceptin), and their application as camptothecin (CPT) delivery agents to human breast cancer SK-BR-3 cells was investigated. Although the diameter of herceptin-modified HNPs (HER-HNP) is smaller than that of other reported mesoporous silica nanoparticles, the extensive hollow cavity of HNPs (ca. 30 nm) allowed the loading of a large amount of CPT. CPT-loaded HER-HNP (HER-HNP-CPT) did not release CPT in phosphate-buffered saline over a period of 24 h, however, HER-HNP-CPT in a hydrophobic solvent released its entire load of CPT. In addition, HER-HNPs were efficiently internalized owing to their herceptin conjugation and optimized size. To evaluate in vitro antitumor efficacy, apoptosis/necrosis and viability of HER-HNP-CPT-treated cells were investigated. When the cells were treated with HER-HNP-CPT for 30 min, a few apoptotic cells were observed. After 24 h, the viability of HER-HNP-CPT-treated SK-BR-3 decreased to 60 %, which revealed highly efficient chemotherapy. However, CPT loaded into HNP or HER-HNP had no significant effects on the viability of macrophages. Judging from these data, HER-HNPs are very suitable for application in anticancer therapy. A HER-HNP-CPT drug delivery system offers a new direction for a hydrophobic anticancer drug carrier and can be expanded to practical applications with further studies.

Lister strain of vaccinia virus armed with endostatin–angiostatin fusion gene as a novel therapeutic agent for human pancreatic cancer

SummarySurvival following pancreatic cancer remains poor despite incremental advances in surgical and adjuvant therapy, and new strategies for treatment are needed. Oncolytic virotherapy is an attractive approach for cancer treatment. In this study, we have evaluated the effectiveness of the Lister vaccine strain of vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapeutic approach for pancreatic cancer. The Lister vaccine strain of vaccinia virus was effective against all human pancreatic carcinoma cells tested in vitro, especially those insensitive to oncolytic adenovirus. The virus displayed inherently high selectivity for cancer cells, sparing normal cells both in vitro and in vivo, with effective infection of tumors after both intravenous (IV) and intratumoral (IT) administration. The expression of endostatin-angiostatin fusion protein was confirmed in a pancreatic cancer model both in vitro and in vivo, with evidence of inhibition of angiogenesis. This novel vaccinia virus demonstrated significant antitumor potency in vivo against the Suit-2 model by IT administration. The present study suggests that the novel Lister strain of vaccinia virus armed with the endostatin-angiostatin fusion gene is a potential therapeutic agent for pancreatic cancer.

Oncolytic Vaccinia Virus Gene Therapy for HNSCC

Problem Oncolytic viral therapy a promising new strategy for the treatment of cancer and an oncolytic adenovirus was first licensed for head and neck squamous cell carcinoma (HNSCC). However, the outcomes of clinical trials with viral monotherapy have been disappointing. Oncolytic vaccinia virus represents an attractive alternative as its replication is less dependent than adenovirus on the genetic make-up of tumor cells and it has been used safely as the smallpox vaccine in millions of patients. Methods The potency and replication of vaccinia virus and adenovirus were compared in a panel of HNSCC cell lines in vitro before assessing the tumor selectivity of systemically delivered vaccinia virus in vivo. In order to increase antitumor potency, a novel vaccinia virus expressing the angiogenesis inhibitory endostatin-angiostatin fusion protein was constructed. The expression and function of this protein was confirmed in vitro and antitumor efficacy assessed in vivo. Results Oncolytic vaccinia virus was more potent than adenovirus against all HNSCC cell lines and displayed high selectivity for cancer cells, sparing normal cells both in vitro and in animal tumour models in vivo. Vaccinia virus expressing the endostatin-angiostatin fusion protein inhibited new blood vessel formation as well as tumour growth by oncolysis. The protein was expressed in virus-infected HNSCC cells and demonstrated function by the inhibition of human umbilical vein epithelial cell proliferation and tube formation in vitro. Treatment of nude mice bearing FaDu HNSCC xenografts significantly prolonged survival when compared to the oncolytic adenovirus ONYX-015 used previously for HNSCC. Conclusion This novel vaccinia virus is a promising therapeutic agent for HNSCC, which improved survival in tumour bearing mice and requires further evaluation in vivo. Significance The combination of an oncolytic vaccinia virus that delivers tumor-specific angiogenesis inhibition may prove to be an effective treatment for patients with HNSCC, with the potential for systemic delivery to treat metastatic disease. Support Cancer Research UK, Royal College of Surgeons of England, Barts and the London Trustees.

Oncolytic vaccinia virus armed with the endostatin‐angiostatin fusion protein; a novel therapy for head and neck cancer

Objectives. The survival of patients with head and neck squamous cell carcinoma (HNSCC) has not improved significantly over recent decades. This had lead to the development of new therapies. Oncolytic viral therapy is a promising new strategy for cancer treatment. The first oncolytic virus licensed for treatment was an adenovirus for HNSCC.1 However, the outcomes of clinical trials using viral monotherapy have been disappointing. Oncolytic vaccinia virus represents an attractive alternative as its replication is less dependent than adenovirus on the genetic make‐up of host cells and it has been used safely as the smallpox vaccine in millions of patients.2Method. This study evaluated the potential of vaccinia virus as a treatment for HNSCC in vitro and in human xenograft models in vivo.Results. The Lister strain of vaccinia virus was more potent than adenovirus against all tumour cells tested in vitro. The virus displayed high selectivity for cancer cells, sparing normal cells both in vitro and in vivo. In order increase antitumour potency, a novel vaccinia virus expressing the endostatin–angiostatin fusion protein was constructed. This inhibits new blood vessel formation as well as tumour growth by oncolysis. The protein was both expressed in virus‐infected tumour cells and demonstrated function by the inhibition of human umbilical vein epithelial cell proliferation and tube formation in vitro.Conclusions. This novel vaccinia virus is a promising therapeutic agent for HNSCC, which requires further evaluation in vivo.References. 1 Garber K. (2006) China approves world's first oncolytic virus therapy for cancer treatment. J. Natl. Cancer Inst. 98, 298–3002 Thorne S.H., Bartlett D.L. & Kirn D.H. (2005) The use of oncolytic vaccinia viruses in the treatment of cancer: a new role for an old ally? Curr. Gene Ther. 5, 429–443